This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The microtubule-associated protein tau abnormally aggregates into fibrillar structures that comprise the neurofibrillary tangles that are a pathological hallmark of Alzheimer's disease and other neurodegenerative diseases. This abnormal protein polymerization is believed to play a direct role in the neurodegenerative process. Therefore, a better understanding of the molecular mechanisms that lead to tau polymerization could have potential benefits to millions of patients afflicted with Alzheimer's disease. To this end, tau polymerization is studied in vitro by inducing filament formation with the addition of anionic co-factors such as arachidonic acid and heparin. These filaments are similar to straight filaments found in Alzheimer's disease in shape, size epitopes that can be identified by antibodies and dyes. However, this research is currently limited by a lack of knowledge of the detailed structure of the tau filaments. It is unclear whether the filaments have a solid core or are hollow;whether the filaments have protofilament structure;whether there is helical symmetry;and the number of subunits per length. Even rudimentary information about the structure of these filaments would enhance Alzheimer's disease research. In the long term, it would be beneficial to investigate the structure of tau filament "intermediates" as compared to tau filaments, to investigate the similarities/differences of filaments induced by arachidonic acid as compared to heparininduced filaments, to investigate the differences in structure of filaments formed from different isoforms of the tau protein, to investigate the effect of post-translational modifications on the structure of the filaments and to compare the structure of filaments with filaments purified from various neurodegenerative tauopathies.